Farming and Movement Evaluation Study (FAME) FAME is a case-control study of PD nested in the Agricultural Health Study (AHS), including 115 PD cases and 384 matched controls. PD diagnosis was verified by movement disorder specialists. Exposure was evaluated using data from the AHS and from additional telephone interviews. Our initial studies focused on pathophysiologic mechanisms implicated in PD by experimental models and genetic studies, including oxidative stress and mitochondrial dysfunction. PD risk was increased 2-fold by pesticides that affect these mechanisms, including the herbicide paraquat and rotenone, an insecticide now used primarily to kill fish. Our results support previous work implicating these mechanisms in PD and provide evidence that certain specific pesticides are associated with PD risk. Personal protective equipment: Protective gloves and workplace hygiene can reduce pesticide exposure. We evaluated whether gloves and hygiene modified the association of PD with use of the pesticides paraquat, permethrin, rotenone, and trifluralin. 61% of respondents consistently used protective gloves and 87% consistently used at least 2 hygiene practices. Protective glove use modified the associations of paraquat and permethrin with PD: neither pesticide was associated with PD among glove users, while both pesticides were associated with 4-fold increase in PD risk among non-users. Rotenone was associated with PD regardless of glove use. Trifluralin increased PD risk among people who used fewer than 2 hygiene practices but not among those using 2 or more practices. Thus protective glove use and hygiene practices may reduce risk of PD associated with certain pesticides. Peptidoglycan recognition proteins (PGRPs) and PD: Increased gut permeability, inflammation, and colonic alpha-synuclein pathology are present in early PD and may contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. PGRPs maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that PGRP genetic variants are associated with PD risk. We genotyped 30 SNPs in the four PGLYRP genes. Three of seven PGLYRP2 SNPs, one of five PGLYRP3 SNPs, and six of nine PGLYRP4 SNPs were significantly associated with PD risk. Association was strongest for PGLYRP4 5-prime untranslated region SNP rs10888557 (GG reference, CG OR 0.6 95%CI 0.4-0.9, CC OR 0.15 95%CI 0.04-0.6; log-additive P-trend, 0.0004). These results are consistent with a role for gut microbiota and gastrointestinal immune response in PD. Other studies in the AHS Air pollutants and PD: We evaluated associations of ozone and fine particulate matter with PD in AHS cohort members. Daily predicted pollutant concentrations were used to derive surrogates of long-term exposure and link them to study participants geocoded addresses. Both pollutants increased PD risk by 30% in North Carolina but not in Iowa. The plausibility of an association of ambient pollutant concentrations on PD risk is supported by experimental data demonstrating damage to dopaminergic neurons at relevant pollutant concentrations. Validation of self-reported cases: Baseline and follow-up AHS questionnaires asked about physician-diagnosed PD. Over 800 individuals reported a diagnosis at least once or else PD was reported on their death certificate. We are screening these individuals or their proxies using a series of questions on symptoms and medication use, which are reviewed by a neurologist to assign a diagnosis. Of 267 reviewed thus far, 224 (84%) received a diagnosis of probable or possible PD. An additional 151 are currently being evaluated, and 50 are being screened. Once the validation project is completed, we will use data from the AHS to evaluate associations of PD risk with pesticides and other neurotoxicants (eg, metals). We will also study whether early symptoms, both motor (tremor, slow movement) and nonmotor (olfaction, sleep problems, depression), predict development of PD and whether pesticide exposure affects this process. We will have a unique opportunity to study the development of PD in the context of ongoing exposure.